Czenke Zoltán, Mándi Attila, Fedics Gergely Miklós, Barta Roland Albert, Kiss-Szikszai Attila, Kurucz-Szabados Anna, Timári István, Bényei Attila, Király Sándor Balázs, Ostorházi Eszter, Zhang Changsheng, Kicsák Máté, Kurtán Tibor
Department of Organic Chemistry, University of Debrecen, P.O. Box 400, 4002 Debrecen, Hungary.
Doctoral School of Chemistry, University of Debrecen, Egyetem tér 1., 4032 Debrecen, Hungary.
Int J Mol Sci. 2025 Aug 12;26(16):7777. doi: 10.3390/ijms26167777.
Inspired by naturally occurring -isochromans such as penicisteckins, we envisaged the first synthesis of biaryl-type -1-arylisochromans containing a stereogenic -trisubstituted biaryl axis. We achieved the stereoselective synthesis of 5,5'-linked heterodimeric -isochromans containing both central and axial chirality elements by performing diastereoselective Suzuki-Miyaura biaryl coupling reactions on two optically active 1-arylpropan-2-ol derivatives, followed by two oxa-Pictet-Spengler cyclizations with aryl aldehydes or methoxymethyl chloride. We studied the diastereoselectivity of the cyclization step, separated the stereoisomeric products with chiral preparative HPLC and determined the absolute configuration through a combination of vibrational circular dichroism (VCD), NMR and single-crystal X-ray diffraction analysis. We demonstrated that different aryl groups could be introduced into the two isochroman subunits, since the dimethoxyaryl subunit reacted faster, enabling the two oxa-Pictet-Spengler cyclizations to be performed separately with different aryl aldehydes. We also explored the acid-catalyzed isomerization and oxidation to axially chiral -quinones in order to produce stereoisomeric and oxidized analogs, respectively. We identified the antibacterial activity of our target -isochromans against and with minimum inhibitory concentrations down to 4.0 and 0.5 μg/mL, respectively, which depend on the stereochemistry and substitution pattern of the -isochroman skeleton.
受天然存在的异色满（如青霉噻唑烷）的启发，我们设想首次合成含有手性三取代联芳基轴的联芳基型-1-芳基异色满。我们通过对两种旋光性1-芳基丙-2-醇衍生物进行非对映选择性铃木-宫浦联芳基偶联反应，然后与芳醛或甲氧基甲基氯进行两次氧杂-Pictet-Spengler环化反应，实现了含有中心和轴向手性元素的5,5'-连接的异二聚体异色满的立体选择性合成。我们研究了环化步骤的非对映选择性，通过手性制备型高效液相色谱分离立体异构产物，并通过振动圆二色性（VCD）、核磁共振和单晶X射线衍射分析相结合的方法确定了绝对构型。我们证明了不同的芳基可以引入到两个异色满亚基中，因为二甲氧基芳基亚基反应更快，使得两次氧杂-Pictet-Spengler环化反应可以分别与不同的芳醛进行。我们还探索了酸催化异构化和氧化为轴向手性醌，以便分别产生立体异构类似物和氧化类似物。我们确定了目标异色满对[具体细菌名称1]和[具体细菌名称2]的抗菌活性，其最低抑菌浓度分别低至4.0和0.5μg/mL，这取决于异色满骨架的立体化学和取代模式。
